DNA Chip May Help Usher In a New Era of Product Testing

Of the 80,000 or so chemicals that go into the products of daily life, the vast majority have never been thoroughly tested for harmful effects. The traditional approach to such testing, exposing laboratory animals to the chemical, is slow, expensive and attacked by animal rights groups. And what happens in animals doesn't always correspond with what happens in people.

But hope is growing among scientists that a new approach -- studying genes -- could offer a faster, cheaper and more accurate way to test drugs, chemicals, food additives and cosmetics.

In the new approach, animals or cells in a test tube are exposed to the chemical. Special chips, known as DNA chips, are then used to see which genes are turned on or off as the animal or cells react. This pattern of gene activity, at least in theory, should indicate whether the chemical is toxic, much as DNA fingerprints are used to judge the guilt or innocence of criminal suspects.

The technique, called toxicogenomics, is still in the early experimental stage, but it could offer many advantages over current approaches. Animal tests, for instance, can determine that a substance causes liver damage, cancer, heart problems or birth defects, but not why it does so. The pattern of gene activity, however, should offer clues to the biochemical pathways by which the harm occurs.

The use of the chips may also reduce the number of animals needed to test chemicals, especially if the tests can be run using cells in the test tube rather than live animals. Still, experts say traditional animal testing may still be needed in some cases to supplement new techniques.

Changes in gene activity may also occur well before other more visible symptoms of harm, like tumors, which can take months to develop. It is also expected that gene tests will be more sensitive to lower doses than animal tests.

''It provides us with a way to do measurements that are much more powerful than we've had before,'' said Dr. Mark D. Johnson, a principal scientist at the R. W. Johnson Pharmaceutical Research Institute in Raritan, N.J., which is part of Johnson & Johnson. ''I would hope that we'd be able to do a much better job of detecting events that are difficult to detect using current methods.''

But the technology could be a mixed blessing for the drug and chemical companies. Experts say that it would be easy for such data to be misinterpreted or incompletely analyzed but that environmental groups would be quick to use the data to urge that products be banned or pollutants more tightly regulated.

''You don't necessarily want to have a more sensitive way to look for poisons,'' said Dr. Chris Bradfield, a professor of oncology at the University of Wisconsin's McArdle Laboratory for Cancer Research. ''There's a lot of trepidation and uncertainty.''

The British arm of Friends of the Earth issued a report earlier this year called ''Crisis in Chemicals,'' in which it argued that genetic studies would make it easier to link a chemical to a disease, increasing the chances of winning liability lawsuits. ''Don't say we didn't warn you,'' the report concludes.

The gene studies may also be used to determine how sensitive an individual is to a particular compound, since that depends on one's genetic makeup.

Such tests will allow doctors to pick medicines that are best for a particular patient. But they will also raise social issues. Should, for example, workers with particular genes be kept out of jobs that entail exposure to certain chemicals? And, regulators may come under pressure to tighten pollution standards to protect the small fraction of the population that is most sensitive to a particular substance.

So even as they work to develop the technology, drug and chemical industry scientists fear that the technique will be used before it is ready and that the data will be misinterpreted, leading to bans on useful drugs or chemicals. ''We have a lot of things that raise red flags,'' said Dr. Joseph F. Sina, editor of the journal In Vitro & Molecular Toxicology and a toxicologist at a major drug company. ''The problem we have is figuring out what red flag is meaningful.''

The risk, experts say, also goes the other way -- that a chip will fail to detect danger that would then be seen after people get exposed.

Genes, made of DNA, instruct the cell to produce proteins, which carry out most functions in the body. The pattern of gene activity can be quickly read by DNA chips. When genes, which are made of DNA, are active they make a chemical messenger called RNA that tells the cell to make a particular protein. By fishing out all this messenger RNA, scientists can tell which genes are active.

The DNA chips are pieces of glass or plastic about the size of a microscope slide that can contain thousands of genes. Usually, the messenger RNA from a cell is converted back to DNA and this DNA is then tagged with a flourescent dye and washed over the chip. Each piece of DNA will stick to the corresponding DNA on the chip, and each spot where this occurs will light up, producing a pattern of lights that show which genes in the cell were on or off.

Such chips are already widely used to understand the causes of disease by comparing, for example, which genes are active in cancer cells but not in healthy cells. Now companies like Affymetrix Inc., the leader in gene chips, and smaller companies like Phase-1 Molecular Toxicology of Santa Fe, N.M., and Xenometrix Inc. in Boulder, Colo., are developing specialized ''tox chips'' or similar test kits that contain just a subset of genes thought to be important in the response to harmful chemicals.

But making sense out of these thousands of points of light is a mind-boggling problem that will probably require computerized pattern matching. Genes turn on and off all the time for various reasons as the body carries out its work. Some gene changes may indeed indicate the cell is in its death throes. But other gene changes could be part of a response that neutralizes the chemical so it does not cause harm.

''There are going to be many changes that have nothing to do with toxicity,'' said Chris Corton, a toxicogenomics researcher at the industry-financed Chemical Industry Institute of Toxicology in Research Triangle Park, N.C.

Dr. Bradfield of Wisconsin pointed to the gene for an enzyme called P450-1A1, which helps the body destroy many chemicals and drugs. That gene is turned on by exposure to dioxin, he said, so drug companies become wary if a drug they are developing activates that gene. But the gene is also turned on by brussels sprouts and many other foods.

To interpret the patterns, scientists are testing hundreds of chemicals with known toxicities to develop a database of genetic signatures against which the unknown compounds can be compared.

Companies like Incyte Genomics of Palo Alto, Calif., and Gene Logic of Gaithersburg, Md., are developing such databases to sell to drug companies. But some experts say that if toxicogenomics is to be used for regulatory decisions, the databases will have to be public.

The National Institute of Environmental Health Sciences, part of the National Institutes of Health, has set up the National Center for Toxicogenomics to do basic research and build a publicly available database.

''We want to build a database that has a large amount of information on compounds and exposures that we know a lot about,'' said Dr. Richard S. Paules, a toxicogenomics researcher at the National Institute of Environmental Health Sciences in Research Triangle Park.

Pharmaceutical and chemical companies also acknowledge the need for a public database. They are participating in a project to build such a database run by the International Life Sciences Institute, a nonprofit organization that works with industry, universities and government agencies.

Right now, no one has really used the technique to predict the toxicity of a chemical. Still, in what scientists say shows that the technique works in principle, early studies are finding that different types of toxic compounds -- hormone disruptors, carcinogens, liver poisons and so on -- have been found to have distinct signatures.

Dr. Johnson of Johnson & Johnson, working with Phase-1 Molecular Toxicology, measured the expression levels of 250 genes after exposing liver cells to 100 known toxic chemicals. A computer, without knowing the identity of the chemicals, could group them by type of toxicity. A paper is appearing in the December edition of the journal Toxicological Sciences.

Boehringer-Ingelheim Pharmaceuticals, working with Phase-1 and the National Institute for Environmental Health Sciences, used the chips to distinguish between two types of toxicity that normally can be distinguished only by time-consuming electron microscope examination of cells, said Raymond E. Stoll, the company's director of toxicology and safety assessment.

Phase-1 found 260 genes that were differentially activated in people allergic to penicillin compared with those not allergic. It has put 20 of those genes with the strongest correlation on a chip that it is considering selling as a penicillin allergy test.

Drug companies are the most enthusiastic users of toxicogenomics. Many clinical trials fail because patients suffer harmful side effects that are not detected in earlier animal tests. And in the last three years, several drugs that were already on the market were removed because they caused harm.

Drug companies typically screen millions of compounds as potential drug candidates. Dr. Spencer B. Farr, chief executive of Phase-1, said tox chips offered a way for such compounds to ''fail fast, fail cheap,'' before millions of dollars were spent on animal and patient tests.

Tularik, a biotechnology company in South San Francisco, Calif., was examining several drug candidates, one of which it knew was toxic. So it compared the others with the toxic one to help eliminate other toxic ones, said Andrew Pearlman, executive vice president.

SmithKline Beecham has already submitted toxicogenomic data to the Food and Drug Administration, though only to supplement data from other, more established tests.

Neither the F.D.A. nor the Environmental Protection Agency is ready to rely on such data, officials said. ''There are a lot of basic quality control issues that have to be addressed,'' said Joseph J. DeGeorge, associate director for pharmacology and toxicology at the F.D.A. The agency is not yet prepared to handle the deluge of data the tox chips can produce. ''Either an animal has tumors or it doesn't,'' he said. ''But each animal can have hundreds of thousand of genes being changed.''

The ultimate role toxicogenomics will play is still unclear. There are other techniques that exist or are being developed as alternatives to animal testing. New animal tests are also in the works, like mice that are being genetically engineered to develop tumors more quickly.

Toxicogenomics is still costly. A commercial chip that tests thousands of genes can cost more than $1,000. And even a simple study would need several such chips to look at the response at several different doses and several points in time after exposure to the chemical. The cost has kept many academics out of the field, although some scientists make their own chips to lower costs. Once relevant genes are identified, however, it should be possible to make small chips containing relatively few genes.

The chips may also miss some reactions. For instance, an adverse side effect of a drug may be caused by its interaction with another drug or by something the drug changes into once inside the body. Testing a single chemical on a toxicology chip may miss such complex interactions.

It is also still unclear how much toxicogenomics will reduce animal use. If the gene tests can be done on cells in a test tube, animals won't be needed. But some types of harmful effects, like inflammation, result from the interaction of different types of cells, so tests on animals will be needed.

Still, for all the uncertainties, many toxicologists think genomics will transform their field. Said Dr. Sina, the journal editor: ''It seems as if it will be the next big screening method.''

Correction: December 1, 2000, Friday An article in Science Times on Tuesday about efforts to use gene tests in predicting the toxicity of chemicals referred incorrectly to an estimate by Joseph J. DeGeorge, an official at the Food and Drug Administration. He said that the activity of ''hundreds or thousands'' of genes -- not hundreds of thousands -- could change in an animal.